In the U.S. population, mortality associated with the 15 most common cancer types alone has been estimated to approach 170 deaths annually per 100,000 individuals. Currently, there are an estimated 1,437,180 new cases of cancer and 565,650 deaths each year. The economic burden of cancer has been estimated to exceed $96B in 1990 dollars.
Adoptive T cell immunotherapy has emerged as a novel cancer therapeutic approach, although its applications are not limited to cancer. Adoptive T cell immunotherapy has the potential to enhance anti-tumor immunity, augment vaccine efficacy and improve the therapeutic effects of chronic infections. There are general three goals for an effective adoptive T cell cancer immunotherapy. First, a sufficient number of potent tumor-reactive T cells must be present in the tumor-bearing host. Second, these tumor-reactive T cells have the capability to reach and infiltrate into the site of the cancer. Third, T cells in the tumor site have appropriate effector mechanisms to destroy cancer cells. Thus, development of novel approaches that augment the persistence, tumor-infiltration and killing activity of tumor-reactive T cells will lead to improving the efficacy of adoptive T cell cancer immunotherapy.
Current available technology to increase the frequency of tumor-reactive T cells from unprimed CD8+ T cells are based on the following two methods: (1) stimulation with polyclonal activators (anti-CD3 and anti-CD28 specific antibodies) and (2) repeated stimulation with antigen-presenting cells loaded with specific antigens. The first method induces the expansion of whole T cell populations in a short time period (7 days or so) without selectively increasing the frequency of antigen-specific T cell clones. The second approach can selectively increase the frequency of antigen-specific T cell clones, but requires 6 weeks to generate sufficient numbers of tumor-reactive T cells for clinical application. Unfortunately, both methods induce the generation of tumor-reactive T cells that display transient cytolytic effects against tumor cells, but cannot persist long enough to destroy the tumor after adoptive transfer.
Thus, there exists an urgent need for improved methods for adoptive T cell immunotherapy, and particularly for methods resulting in generation and transfer of tumor-reactive T cells that are both cytolytic against target cells and that have the ability to persist in vivo for sufficiently long periods of time.